Tamoxifen, a nonsteroidal antiestrogen, is commonly used in the treatment of breast cancer in postmenopausal women and has been associated with a significant reduction of cardiovascular events in several breast cancer treatment trials. Although this effect may be due in part to favorable alteration of plasma lipoprotein concentrations to a less atherogenic profile, tamoxifen also inhibits lipid and human low density lipoprotein (LDL) oxidation in vitro, albeit at suprapharmacologic concentrations. We studied whether tamoxifen, orally administered to postmenopausal women, has antioxidant effects on their LDL, comparing its effect to that of conjugated equine estrogen in a randomized, double-blind, placebo-controlled crossover trial. The time to onset of LDL peroxidation was assessed by an in vitro assay. The time to onset of LDL peroxidation was measured in 24 postmenopausal women following 2 months treatment with daily tamoxifen 20 mg, conjugated equine estrogen 0.65 mg, and identical placebo taken in random order in 3 time periods. A one month washout period followed each treatment period. Tamoxifen and conjugated equine estrogen lowered LDL levels by 19% and by 13% respectively. Conjugated equine estrogen also increased high density lipoproteins by 13% compared to placebo. Time to onset of LDL oxidation differed from placebo only during the tamoxifen treatment: the onset of LDL oxidation was 20% longer on tamoxifen compared with placebo. Tamoxifen had significant carry-over effect on subsequent treatment periods: thus, although tamoxifen appeared to have no effect in the 11 subjects who received tamoxifen prior to placebo, in the 13 patients who received placebo prior to tamoxifen, compared to placebo tamoxifen increased the onset of LDL oxidation by 32% and reduced the maximum rate of oxidation by 28%. No correlation was found between the antioxidant effect of tamoxifen and the change in LDL concentrations on tamoxifen treatment. This study provides evidence of potent and prolonged antioxidant effects of tamoxifen on LDL when administered in conventional dosage to postmenopausal women. These effects are independent of changes in LDL concentration and may contribute to reduction of cardiovascular events on this drug.